Glucose Metabolism in Autism

Vitamin B2 and Glucose metabolism

Glucose is metabolized via the glycolysis parthway

The final step in glycolysis is the formation of pyruvate

Pyruvate is converted to AcetylCoA by the B2/B1/lipoate dependent enzyme Pyruvate Dehydrogenase
Deficiency of functional B2 deficiency reduces the activity of pyruvate dehydrogenase, and increases lactic acid conversion from pyruvate
Functional B2 deficiency can result in Gestational diabetes in the mothers.
Glucose stored as Glycogen, is released by the P5P-dependent enzyme Glycogen phosphorylase
The children can be born with poor glucose metabolism, due to the inability to process stored glycogen, or inability to properly process pyruvate.

Vitamin B2 and Glycolysis

Following ingestion, dietary glucose enters the circulation and is taken up via specific glucose transporters. In glucose excess in the circulation, insulin is released, binds to insulin receptors on appropriate cells, which then turns on inducible glucose transporters. Once inside the cell, glucose either enters the glycolysis pathway, or in glucose excess is stored as glycogen. Glucose then enters glycolysis, and is processed to generate 2 molecules of pyruvate, which in the presence of vitamin B2 (as FAD), vitamin B1 (as TPP) and lipoate, is processed by the enzyme pyruvate dehydrogenase to form acetyl CoA. In functional B2 deficiency, however, the pyruvate is rapidly converted to lactic acid, which then down-regulates the expression of the glucose transporter and the cell can then become refractory to insulin. As serum glucose drops, glucose, stored as glycogen can be released to form glucose-1-phosphate by the action of the P5P-dependent enzyme glycogen phosphorylase. In functional B2 deficiency, however, Pyridoxal is not converted to Pyridoxal phophate (P5P) and so glucose cannot be obtained from glycogenolysis. In this situation, serum glucose will be lower and a state of hypoglycemia will result. Hypoglycemia is common in children with autism (Hodax etal 2007; Lee etal, 2022; Guevara-Campos etal, 2019; Yalįın etal, 2022; Tish etal, 2019; Garbarino etal 2022; Good 2011) which can often be preceded by gestational diabetes in the mothers (Buchmayer et al, 2009; Garbarino etal, 2022

Fate of Ingested Glucose

Alteration in glycolysis and glycogenolysis in functional vitamin B2 deficiency.

Comparison of glutaric acid, a standard marker of vitamin B2 deficiency, with levels of lactic acid in the urine of ASD children reveals a bi-phasic pattern, in which initially there is a huge rise in lactic acid levels, however, as glutaric acid rises about 0.5, there is a sudden drop in levels, suggesting that at this point, there is insufficient activity of glycogen phosphorylase to release glucose from stored glycogen

Comparison of glutaric acid (x axis) with lactic acid levels (y axis).

There are a number of other markers that associated with low functional vitamin B2 that show a similar profile to that for lactic and glutaric.

Comparison of glutaric acid (x axis) with Kynurenic acid (KA, y axis)

Comparison of Glutaric acid (x axis) to QA:KA ratio (y axis)

Comparison of Glutaric acid (x axis) with succinic acid (y axis).

Hypoglycemia is common in autism, and the data presented above would support other findings of functional vitamin B2 in autism. Hence if functional B2 was sufficiently bad, then metabolism of glucose via glycolysis would be reduced, and release of glucose from glycogen would also be reduced. This would then be associated with poor energy metabolism in the brains of the children with autism, compounding the observed developmental delay. Analysis of mean serum glucose levels may not reveal these correlations as the elevated lactic acid would be "normalized" by the much lower lactic acid seen in extreme functional B2 deficiency.

References

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